1. Field of the Invention
The present invention relates to a pharmaceutical composition for regeneration of nerves or acceleration growth of axons comprising Vax protein as an active ingredient, and a method for screening candidates for the regeneration of nerves or acceleration growth of axons by using Vax protein.
2. Description of the Related Art
The binocular visual system of mammals is formed by the topographic synaptic connection between the neurons of dorsal lateral geniculate nucleus (dLGN) and superior colliculus (SC) and the retinal ganglion cell (RGC) axon. In order for the retinal ganglion cell axon to contact with the target synapse, it recognizes neuroaxon growth guidance cues expressed in optic pathway structure including optic disc (OD), optic stalk (OS), optic chiasm (OC), and optic tract (OT), and then the axon is growing out of retina to the selected direction (Lemke and Reber, 2005; Petros et al., 2008). The said retinal ganglion cell axon guidance cues are exemplified by the cell surface ligands such as semaphorin existing in optic stalk and ephrinB2 exiting in optic chiasm; or the secreted factors such as netrin-1 existing in optic disc and Slit1 existing in optic chiasm (Erskine and Herrera, 2007). However, approximately only 3% of the retinal ganglion cell axon originated from the ventral and temporal areas of mouse retina proceeds to the ipsilateral hemisphere and the rest of it proceeds to the contralateral hemisphere across the midline of ventral hypothalamus where optic chiasm resides.
Ventral hypothalamus cells express those molecules that are responsible for the determination of the direction of retinal ganglion cell axon progress in optic chiasm. For example, ventral hypothalamus radial glial cells express ephrinB2 that binds to EphB1 receptor expressed in the ventral-temporal retinal ganglion cell axon to make the axon heading for ipsilateral optic track retreat (Nakagawa et al., 2000; Williams et al., 2003). In the meantime, the vascular endothelial growth factor 164 (VEGF164) and neuronal cell adhesion molecule (NrCAM) expressed in ventral hypothalamus bind to Neurophilin 1 and Plexin A1 respectively to induce the growth of retinal ganglion cell axon across the ventral hypothalamus midline (Erskine et al., 2011; Kuwajima et al., 2012; Williams et al., 2006). The retinal ganglion cell axon has to pass the ventral-lateral diencephalic area highly expressing repulsive signals such as Slit and sephaphorin in order to receive the direction guidance signals from those molecules in optic chiasm (Erskine and Herrera, 2007). However, those molecules of ventral diencephalic area that induce retinal ganglion axon to grow to the direction of midline with overcoming the repulsive signals have not been identified, yet.
Vax1 (ventral anterior homeobox 1) is a homeodomain transcription factor expressed in various ventral-medial forebrain originated structures including medial and lateral geniculate eminence (MGE and LGE), ventral septum, anterior entopeduncular area (AEP), preoptic area (POA), ventral hypothalamus, and optic disc (Bertuzzi et al., 1999; Hallonet et al., 1998). The genetic malfunction of Vax1 in human and mouse causes not only coloboma of the eye but also agenesis of multiple midline structures of the brain including anterior commissure, corpus callosum, and optic chiasm (Bertuzzi et al., 1999; Hallonet et al., 1999; Slavotinek et al., 2012). In a Vax1 knock out mouse, the retinal ganglion cell axon can grow over optic disc but cannot reach ventral hypothalamus and at last fails in the formation of optic chiasm. Vax1 plays an important role in the growth and fasciculation of retinal ganglion cell axon, but is not expressed in retinal ganglion cells (Bertuzzi et al., 1999).